In adults there is a striking concordance in the trajectories and connectivity of sensory and motor neurons and their target muscles in the limb. Whereas much is known about cellular processes responsible for the development of this pattern, identification of the molecular signals is in its infancy. The goal of this proposal is to characterize the role of selected members of two molecular families -- Eph receptor tyrosine kinases and ETS transcription factors -- in developmental events that lead to the exquisite matching of sensory and motor pathways and connections in a classical model system, the chick hindlimb. Eph receptors and ephrins show complex patterns of expression in limb and in sensory and motor neurons. Aim I is to assess the contribution of Eph receptors, in particular EphA7, and ephrins in patterning axon growth in the limb. Expression or function of EphA receptors or ephrins will be manipulated, and the resulting innervation patterns will be assessed. Alterations in innervation patterns would provide evidence that Eph receptors or ephrins are involved in patterning axon growth in the limb. The ETS transcription factors ER81 and PEA3 are expressed in monosynaptically-connected sensory and motor neurons, and are required for formation of these connections. Aim II is to determine the nature of signals from the limb that regulate ETS expression, and whether these factors determine the specificity of sensory-motor connections. ETS expression will be assayed with antibody staining or in situ hybridization after surgical manipulations in ovo. CNS connectivity will be assayed electrophysiologically. Alterations in ETS expression would show that signals from the limb determine this pattern. Concordance of ETS expression in monosynaptically-connected sensory and motor neurons would suggest that ETS proteins confer specificity to these connections. These studies will elucidate molecular mechanisms involved in the normal development of limb innervation patterns. This information should be applicable to more complex neural circuits involved in behavior and higher order functions. Moreover, knowledge gained here will provide insight in the design and implementation of therapeutic strategies to promote axon growth and to restore innervation and function following nerve injury or disease.